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WO2018209074A1 - Imidazo[4,5-b]pyridin-2-yl amides utilisés en tant qu'activateurs du canal kv7 - Google Patents

Imidazo[4,5-b]pyridin-2-yl amides utilisés en tant qu'activateurs du canal kv7 Download PDF

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Publication number
WO2018209074A1
WO2018209074A1 PCT/US2018/032050 US2018032050W WO2018209074A1 WO 2018209074 A1 WO2018209074 A1 WO 2018209074A1 US 2018032050 W US2018032050 W US 2018032050W WO 2018209074 A1 WO2018209074 A1 WO 2018209074A1
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Prior art keywords
disorder
compound
pharmaceutically acceptable
acceptable salt
subject
Prior art date
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PCT/US2018/032050
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English (en)
Inventor
James S. Hale
Lynn Resnick
George T. Topalov
David A. Mareska
Charles A. Flentge
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Knopp Biosciences LLC
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Knopp Biosciences LLC
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Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • Potassium (jC) channels present on the plasma membranes of most cell types, are the most diverse class of all ion channels and are associated with a wide range of physiological functions including the regulation of the electrical properties of excitable cells.
  • the primary pore-forming (a) subunits of these highly selective cation channels are divided into three primary structural classes based on the number of transmembrane (TM)-spanning regions and pore (P) regions: currently there are known to be 6TM/1P, 2TM/1P and 4TM/2P K + channels.
  • Kv7 genes (originally termed KCNQ, a name assigned by the HUGO Gene Nomenclature Committee (HGNC)) were assigned to a subfamily of voltage-gated K + channels by the International Union of Pharmacology (IUPHAR).
  • the Kv7 subfamily consists of five homologous pore-forming a subunits, Kv7.1-7.5, that have a structure typical of voltage-gated K + channels with 6TM-spanning regions (S1-S6) flanked by intracellular N- terminal and C-terminal domains, a typical voltage-sensor domain located in S4 comprised of alternating positively-charged residues and a single P region between S5 and S6 of each subunit.
  • the channels are formed as tetramers of the primary a subunits, either as homotetramers or heterotetramers.
  • Neurons are known to express Kv7 channels comprised of Kv7.2-7.5 a subunits. Some of these gene products may be exclusively neuronal while others, such as Kv7.4 and Kv7.5, can be found in other tissues such as smooth and skeletal muscle.
  • Retigabine is modestly potent, not highly specific, but it is a very effective opener of Kv7.2, Kv7.5, and heteromultimeric Kv7 channels.
  • compounds that can be potent and/or at least biased for the Kv7.2/7.3 heteromultimer over the Kv7.4 homomultimer. These compounds may have reduced untoward side effects as compared to retigabine.
  • administering when used in conjunction with a therapeutic, means to administer a therapeutic directly into or onto a target tissue or to administer a therapeutic to a subject whereby the therapeutic positively impacts the tissue to which it is targeted.
  • a composition may be accomplished by oral administration, injection, infusion, absorption or by any method in combination with other known techniques.
  • administering ' may include the act of self-administration or administration by another person such as a healthcare provider or a device.
  • the term "consists of or “consisting of means that the composition or method includes only the elements, steps, or ingredients specifically recited in the particular embodiment or claim.
  • composition or method includes only the specified materials or steps and those that do not materially affect the basic and novel characteristics of the claimed invention.
  • compositions and methods may be utilized with or on a subject in need of such treatment, which may also be referred to as "in need thereof.”
  • in need thereof means that the subject has been identified as having a need for the particular method or treatment and that the treatment has been given to the subject for that particular purpose.
  • the term "patient” and “subject” are interchangeable and may be taken to mean any living organism, which may be treated with compounds of the present invention.
  • the terms '"patient” and “subject” may include, but is not limited to, any non-human mammal, primate, or human.
  • the "patient” or “subject” is an adult, child, infant, or fetus.
  • the "patient” or “subject” is a human.
  • the "patient” or “subject” is a mammal, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, or humans.
  • terapéuticaally effective amount or “therapeutic dose” is used herein are interchangeable and may refer to the amount of an active agent or pharmaceutical compound or composition that elicits a clinical, biological or medicinal response in a tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, medical doctor, or other clinical professional.
  • a clinical, biological, or medical response may include, for example, one or more of the following: (1) preventing a disease, condition, or disorder in an individual that may be predisposed to the disease, condition, or disorder but does not yet experience or display pathology or symptoms of the disease, condition, or disorder, (2) inhibiting a disease, condition, or disorder in an individual that is experiencing or displaying the pathology or symptoms of the disease, condition, or disorder or arresting further development of the pathology and/or symptoms of the disease, condition, or disorder, and (3) ameliorating a disease, condition, or disorder in an individual that is experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder or reversing the pathology and/or symptoms experience or exhibited by the individual.
  • treating may be taken to mean prophylaxis of a specific disorder, disease, or condition, alleviation of the symptoms associated with a specific disorder, disease or condition, and/or prevention of the symptoms associated with a specific disorder, disease, or condition.
  • the term refers to slowing the progression of the disorder, disease, or condition or alleviating the symptoms associated with the specific disorder, disease, or condition.
  • the term refers to alleviating the symptoms associated with the specific disorder, disease, or condition.
  • the term refers to alleviating the symptoms associated with the specific disorder, disease, or condition.
  • the term refers to restoring function which was impaired or lost due to a specific disorder, disorder, or condition.
  • “Pharmaceutically acceptable salt” is meant to indicate those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a patient without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. (1977) J. Pharm. Sciences, Vol. 6, 1-19, describes pharmaceutically acceptable salts in detail.
  • a pharmaceutical acceptable “salt” is any acid addition salt, preferably a pharmaceutically acceptable acid addition salt, including, but not limited to, halogenic acid salts such as hydrobromic, hydrochloric, hydrofluoric, and hydroiodic acid salt; an inorganic acid salt such as, for example, nitric, perchloric, sulfuric, and phosphoric acid salt; an organic acid salt such as, for example, sulfonic acid salts (methanesulfonic, trifluoromethan sulfonic, ethanesulfonic, benzenesulfonic, or p-toluenesufonic, acetic, malic, fumaric, succinic, citric, benzonic gluconic, lactic, mandelic, mucic, pamoic, pantothenic, oxalic, and maleic acid salts; and an amino acid salt such as aspartic or glutamic acid salt.
  • halogenic acid salts such as hydrobromic, hydroch
  • the acid addition salt may be a mono- or di-acid addition salt, such as a di-hydrohalogic, di-sulfuric, di-phosphoric, or di-organic acid salt.
  • the acid addition salt is used as an achiral reagent which is not selected on the basis of any expected or known preference for the interaction with or precipitation of a specific optical isomer of the products of this disclosure.
  • Embodiments herein are directed to pharmaceutical compositions comprising a therapeutically effective amount of a compound described herein or acceptable salts thereof, such as a compound of paragraph [0016] or Table 1 or pharmaceutically acceptable salts thereof.
  • Pharmaceutical compositions containing such compounds and a suitable carrier can be in various forms including, but not limited to, solids, solutions, powders, fluid emulsions, fluid suspensions, semi -solids, and dry powders including an effective amount of a compound of the invention.
  • the active ingredients can be contained in such formulations with pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, antioxidants, preservatives, and the like.
  • Hie means and methods for administration are known in the art and an artisan can refer to various pharmacologic references for guidance. For example. Modem Pharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979); and Goodman & Oilman's, The Pharmaceutical Basis of Therapeutics, 6th Edition, MacMillan Publishing Co., New York (1980) both of which are hereby incorporated by reference in their entireties can be consulted.
  • the compounds can be formulated for parenteral or intravenous administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and/or dispersing agents.
  • Injectable preparations may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • a nontoxic parenterally acceptable diluent or solvent for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • compositions include a compound prepared as described above which are formulated as a solid dosage form for oral administration including capsules, tablets, pills, powders, and granules.
  • the active compound may be admixed with one or more inert diluent such as sucrose, lactose, or starch.
  • Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents and can additionally be prepared with enteric coatings.
  • Preparation of a compound of the invention in solid dosage form may vary.
  • a liquid or gelatin formulation may be prepared by combining a compound, such as those described above, and adding a thickening agent to the liquid mixture to form a gelatin. The gelatin may then be encapsulated in unit dosage form to form a capsule.
  • an oily preparation of a compound prepared as described above may be lyophilized to for a solid that may be mixed with one or more pharmaceutically acceptable excipient, carrier or diluent to form a tablet.
  • Further embodiments which may be useful for oral administration of a compound for the invention include liquid dosage forms.
  • a liquid dosage may include a pharmaceutically acceptable emulsion, solution, suspension, syrup, and elixir containing inert diluents commonly used in the art, such as water.
  • Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
  • the compounds described herein can be formulated as a depot preparation.
  • Such long acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Depot injections can be administered at about 1 to about 6 months or longer intervals.
  • the compounds can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • Embodiments of the present invention relate to a method of treating a disorder comprising administering a therapeutically effective amount of a compound as described in paragraph [0016] or Table 1, or any other compound as described herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • the disorder is selected from epilepsy, epileptic spasms, neonatal spasms, neonatal seizures, benign familial neonatal epilepsy, epileptic encephalopathy, pain, migraine, a disorder of neurotransmitter release, a smooth muscle contractility disorder, early infantile epileptic encephalopathy with delayed psychomotor development, generalized tonic seizures, abnormal globus pallidus morphology, apnea, cerebral edema, a dyskinesia, dystonia, facial erythema, muscular hypotonia, febrile seizures, hypoplasia of the corpus callosum, hypsarrhythmia, focal clonic seizure, generalized tonic-clonic seizures, myokymia, spastic tetraparesis, myokymia, mania, a hearing disorder, neuropathic pain, inflammatory pain, persistent pain, cancer pain, postoperative pain, anxiety, substance abuse, schizophrenia, a bladder disorder, a vasculature disorder
  • KCNQ genes encode five Kv7 potassium channel subunits (1-5).
  • a functional Kv7 potassium channel can be assembled using a combination of these five subunits arranged as homotetramers or heterotetramers.
  • KCNQ2, KCNQ3, KCNQ4, and KCNQ5 are expressed in the nervous system and have been associated with a range of disorders involving neuronal excitability.
  • Embodiments herein are directed to methods of treating a disorder associated with a KCNQ subunit comprising administering a therapeutically effective amount of a compound as described in paragraph [0016] or Table 1, or any other compound as described herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • Embodiments herein are directed to methods of treating a disorder associated with a KCNQ2 subunit comprising administering a therapeutically effective amount of a compound as described in paragraph [0016] or Table 1, or any other compound as described herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • Embodiments herein are directed to methods of treating a disorder associated with a KCNQ3 subunit comprising administering a therapeutically effective amount of a compound as described in paragraph
  • Embodiments herein are directed to methods of treating a disorder associated with a KCNQ4 subunit comprising administering a therapeutically effective amount of a compound as described in paragraph [0016] or Table 1, or any other compound as described herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • Embodiments herein are directed to methods of treating a disorder associated with a KCNQS subunit comprising administering a therapeutically effective amount of a compound as described in paragraph [0016] or Table 1, or any other compound as described herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • Embodiments herein are directed to methods of treating a disorder associated with a mutation in a KCNQ subunit comprising administering a therapeutically effective amount of a compound as described in paragraph [0016] or Table 1, or any other compound as described herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • Embodiments herein are directed to methods of treating a disorder associated with a mutation in a KCNQ2 subunit comprising administering a therapeutically effective amount of a compound as described in paragraph [0016] or Table 1, or any other compound as described herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • Embodiments herein are directed to methods of treating a disorder associated with a mutation in a KCNQ3 subunit comprising administering a therapeutically effective amount of a compound as described in paragraph [0016] or Table 1, or any other compound as described herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • Embodiments herein are directed to methods of treating a disorder associated with a mutation in a KCNQ4 subunit comprising administering a therapeutically effective amount of a compound as described in paragraph [0016] or Table 1, or any other compound as described herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • Embodiments herein are directed to methods of treating a disorder associated with a mutation in a KCNQ5 subunit comprising administering a therapeutically effective amount of a compound as described in paragraph [0016] or Table 1, or any other compound as described herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • such compound may be administered in a pharmaceutical composition as described herein.
  • Therapeutically effective amounts of the compounds disclosed herein range from about 0.1 mg to about 1000 mg. Such therapeutically effective amounts may be administered once a day or in equal, divided doses twice a day, three times a day, or four times a day.
  • Cell Culture Cells were maintained in a media containing DMEM/F12; 50/50 (GIBCO cat.# 11330), 10% Fetal Bovine Serum (FBS) (GIBCO catJ 26140), 100 units/mL Penicillin-Streptomycin (GIBCO cat.# 15140), 0.005 mg/rtiL Blasticidin (INVIVOGEN catJ ant-bl-1), 0.5 mg/mL Geneticin (GIBCO cat.# 10131), 0.1 mg/mL Zeocin (GIBCO catJ R25001).
  • Cells used in the electrophysiology assay were maintained in a media without Blasticidin, Geneticin and Zeocin for 2 days and channel expression was induced by adding tetracycline (BIOLINE cat.# BIO-87030) at a final concentration of 1 mg/mL. Cells were grown in T-175 flask to ⁇ 75% confluency. Currents were recorded 24 hours after channel induction.
  • Test compounds were prepared by performing serial dilutions on a Biomek NX P (BECKMAN COULTER). Final dilutions were made in external recording solution with a final DMSO concentration of 0.1% DMSO. For single concentration screens each plate had 10 ⁇ retigabine as a positive control and 0.1% DMSO as a negative control.
  • External recording solution contained (in mM): NaCl (145), KC1 (4), CaCl 2 (2), MgCl 2 (1), HEPES (10) and Glucose (10); pH was adjusted to 7.4 with NaOH and the osmolality was adjusted to 300-305 mOsM with sucrose if necessary.
  • Internal solution contained (in mM): KC1 (125), KF (10), EGTA (5), Na2ATP (5), MgC.2 (3.2), HEPES (5); pH was adjusted to 7.2 with KOH and the osmolality was adjusted to 298-302 mOsM with sucrose.
  • Potassium channel activity was measured on the QPatch HTX (Sophion Bioscience) using QPlates with 48-wells/plate. Each cell was taken as an independent experiment and only one compound was tested per well. Potassium channel activity was elicited by holding at -80 mV and stepping to -30 mV for 2 s followed by a 100 ms pulse to - 120 mV.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des benzoimidazol-1,2-yl amides éventuellement substitués, tels que des composés de l'invention (par exemple, des composés du tableau 1), qui peuvent être utilisés pour traiter des troubles associés aux troubles d'excitabilité neuronale, des sous-unités de canal KCNQ ou des mutations dans le gène KCNQ qui codant pour le canal potassique Kv7. Selon des modes de réalisation, la présente invention concerne également des compositions pharmaceutiques des composés du tableau 1.
PCT/US2018/032050 2013-03-15 2018-05-10 Imidazo[4,5-b]pyridin-2-yl amides utilisés en tant qu'activateurs du canal kv7 Ceased WO2018209074A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201361793892P 2013-03-15 2013-03-15
US15/591,884 US10106536B2 (en) 2013-03-15 2017-05-10 Imidazo(4,5-B) pyridin-2-yl amides as KV7 channel activators
US15/591,884 2017-05-10

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WO2018209074A1 true WO2018209074A1 (fr) 2018-11-15

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PCT/US2014/030686 Ceased WO2014145852A2 (fr) 2013-03-15 2014-03-17 Imidazo(4,5-b) pyridine-2-yl amides en tant que d'activateurs du canal kv7
PCT/US2018/032050 Ceased WO2018209074A1 (fr) 2013-03-15 2018-05-10 Imidazo[4,5-b]pyridin-2-yl amides utilisés en tant qu'activateurs du canal kv7

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EP (1) EP2970277B1 (fr)
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US10106536B2 (en) 2018-10-23
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EP2970277B1 (fr) 2021-07-28
US20170240547A1 (en) 2017-08-24
US20190002464A1 (en) 2019-01-03
US10526328B2 (en) 2020-01-07
WO2014145852A2 (fr) 2014-09-18
ES2885424T3 (es) 2021-12-13
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EP2970277A2 (fr) 2016-01-20
US20160031875A1 (en) 2016-02-04

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